Cancer is a class of diseases characterized by the uncontrolled division of the affected cells and the ability of these cells to spread, either by invasion, the direct growth of the cancer or neoplastic cells into unaffected tissue or by metastatic growth, the implantation of metastatic cells into distant sites. While there are various therapies and pharmaceuticals developed to treat cancer, the variability of the disease, from tissue to tissue and its ability to develop metastatic growths in distant location together with its resistance to drugs and therapies has resulted in an enormous amount of research to identify therapies or drugs that are effective in a wide variety of cancers and that are non-toxic or at least non-fatal to healthy cells.
Phospholipids are the major lipid component of cell membranes. Ether phospholipids are a minor phospholipid subclass differing by having an ether linkage at the C-1 carbon of the glycerol backbone rather than the normal ester bond. Alkyl phosphocholines (APC), for example, hexadecylphosphocholine (HPC), are another subclass of compounds that have shown antineoplastic targeting activity. Assessment of this new class of PLE analogs as cancer treatments in several animal tumor models provided by the inventors revealed that NM404 (18-[4-Iodophenyl]-octadecyl phosphocholine) and similar PLE and APC analogs, specifically accumulate and are selectively retained in primary and/or metastatic tumors. While some compounds such as, fluorodeoxyglucose (FDG) are commonly used in imaging applications for its high uptake in cancer tissues, FDG also accumulates in inflammatory and granulomatous lesions thereby giving false positives, does not accumulate in bone metastases of prostate cancer and further, is rapidly cleared in the urine thereby resulting in a short time frame for use and also in high background in the kidneys and bladder. Further, FDG also has no therapeutic potential and its clinical use is solely as a means of imaging it incorporation into high metabolic tissues. Thus, FDG can not begin to approach the specificity and versatility of PLE and APC analogs.
Further investigation of radioiodinated PLE and APC analogs, such as radioiodinated NM404 has demonstrated, in 37 of 37 models investigated, a remarkable tumor selectivity of these compounds in a wide variety of tumor models. See, for example, U.S. patent application Ser. Nos. 10/906,687, 11/177,740, 11/316,620 and 11/382,645. Due to deficiencies in metabolic phospholipase enzymes in the membranes of malignant tumor cells, the prevailing hypothesis for this specificity is that phospholipid ether analogs become trapped exclusively in tumor cell membranes because of their inability to become metabolized and eliminated by the cancerous cell. Thus, the differential clearance rates of phospholipid ethers from normal cells versus neoplastic tumor cells are responsible for this specificity. Results obtained in a variety tumor models indicate that PLE and APC analogs, such as, NM404 are sequestered and selectively retained by viable tumor cells and localize in both primary and metastatic lesions regardless of anatomic location including those found in lymph nodes.
One recognized treatment for cancer is radiotherapy which uses ionizing radiation to kill cancer cells. Such treatments can be given in a variety of ways, such as X-rays, gamma rays, neutron beams or implanted particles. While radiation therapy is used in over half of all cancer patients it is limited by its inability to specifically and precisely target cancer cells and thereby limit its toxicity to healthy tissue. In an effort to limit radiation administered to healthy tissues during treatment by external radiation, methods for internal radiation treatment are being developed. For example, endocavitary radiation therapy (Endo RT) and endo-luminal RT can be performed on select individual and is preformed by the insertion of a contact X-ray tube into a tumor or into tubular structures such as the bronchi or esophagus to limit the deleterious effect of radiation on healthy cells. However, with both external radiation and with endo radiation therapy the radiation dose is delivered non-specifically to the region proximate to the tumor but not delivered specifically or selectively to the metastatic cells. Further, in an effort to solve the problem of non-specific radiation, radioimmunotherapy—radioactive antibodies—have been developed that are specific for epitopes displayed by neoplastic cells. However, while antibodies have exquisite specificity, their specificity is directed to only to a single cognate epitope which is specific for each neoplastic cell type. Thus, neither of the methods described above are adequate for the systemic administration of cancer therapies specifically directed to neoplastic cells.
Boron neutron capture therapy (BNCT) is a binary radiation therapy having two components each of which, independently, has only minor effects on cells. BNCT utilizes the neutron capture by which a neutron collides with an atomic nucleus, boron, to produce alpha particles, lithium nuclei and ionizing radiation. Both the alpha particle and the lithium ion produce closely spaced ionizations in the vicinity of the reaction, approximately 10 μm, or the diameter of a cell. Therefore, the ability to target and sequester the boron atom in the cancer cell would allow the products of the neutron bombardment to specifically irradiate cancer cells.
External beam radiation therapy is similar to BNCT in that linear accelerators are used to produce a beam of electrons that can be focused to hit a desired target. When the target is an appropriate alloy (such as 10B), collision results in the liberation of gamma radiation. Gamma rays are characterized by a short wavelength and high energy. Due to their high energy, the liberated gamma rays provide lethal radiation only to adjacent tissue.
Currently, one limitation of BNCT and external beam radiation is the ability to specifically target cancer cells and limit the deleterious effects of the radiation in surrounding healthy tissue.